Molecular Effect of Exercise

Study Notes

Exercise produces signaling molecules in response to muscle contraction, influencing its own metabolism and the metabolisms of other tissues and organs.
Exercise can induce dynamic remodeling in the cellular composition of tissues and vasculature, affecting data interpretation across multiple omics applications.

Low-Load Endurance Exercise:
- Characterized by an increase in structures supporting oxygen delivery (capillaries) and consumption (mitochondria).
- Examples include running, cycling, rowing, swimming, and cross-country skiing.
High-Load Strength Exercise:
- Characterized by growth of muscle fibers, primarily through an increase in the amount of contractile proteins.
- Mitochondria are the cellular organelles that provide much of the energy in our cells.

Adaptive response of cells to intermittent stress, resulting in increased mitochondrial metabolism and reduced reactive oxygen species (ROS).
Key players in mitohormesis include:
- Peroxisome proliferator-activated receptor Gamma Coactivator-1alpha (PGC-1), which regulates key genes in skeletal muscles.
- Nuclear factor erythroid 2-related factor 2 (Nrf2), which activates various genes that encode antioxidant enzymes.

Mitochondrial content and capillary content are highly correlated in skeletal muscle.
Key players in angiogenesis include:
- Vascular Endothelial Growth Factor (VEGF), which triggers capillary growth.
- Hypoxia-inducible factor-1 (HIF-1), which induces transcription of target genes involved in erythropoiesis, angiogenesis, glycolysis, and energy metabolism.

Skeletal muscle is an endocrine organ that produces signaling molecules (myokines) in response to contraction.
Myokines influence its own metabolism and the metabolisms of other tissues and organs.
Examples of myokines include:
- Interleukin-6 (IL-6), which stimulates both glucose and lipid metabolism.
- IL-6 promotes hypertrophy by stimulating proliferation of muscle stem cells (satellite cells) and by augmenting the rate of protein synthesis.

Satellite cells are a heterogeneous population of cells that undergo symmetric division and differentiation in response to stimulation.
Strength training increases skeletal muscle fiber cross-sectional area and satellite cell number.
Androgens are steroids that promote satellite cell activation and proliferation, further supporting skeletal muscle hypertrophy.

Several kinases are activated in response to exercise, including:
- Adenosine monophosphate (AMP)-activated protein kinase (AMPK)
- Protein kinase A (PKA)
- Calcium/calmodulin-dependent protein kinase (CaMK)
- Mitogen-activated protein kinase (MAPK)
- Protein kinase C (PKC)
- Mammalian target of rapamycin (mTOR)
AMPK activation through physical exercise improves mitochondrial biogenesis through the regulation of PGC-1α.
CaMK-II promotes lipid uptake and oxidation, and skeletal muscle also triggers regulation of important transcription factors, such as the cyclic AMP response element-binding protein (CREB), MEF2, and HDACs.

Endurance training activates the AMPK-MAPK-PGC-1α signaling cascades, leading to increased mitochondrial biogenesis and metabolic adaptations.
Resistance training increases the activation of the phosphoinositide 3-kinases Protein kinase B–mTOR (PI3k-Akt-mTOR) signaling cascade, regulating the rate of protein synthesis and/or degradation and consequently, muscle hypertrophy.

Epigenetics is the study of changes in transcriptional expression and/or activity without variation in DNA sequence.
Epigenetic modifications include:
- DNA methylation
- Histone modifications (acetylation, methylation, phosphorylation, lactylation)
- Micro-RNAs

DNA methylation results in the stable silencing of gene expression by repressing transcription.
Exercise generally results in DNA hypomethylation in key skeletal muscle genes, representing an early response that mediates skeletal muscle adaptations to exercise.

Histone acetylation is a transient enzymatic process that is associated with gene activation.
Histone methylation can activate or repress gene transcription depending on the proteins they recruit to chromatin.
Histone phosphorylation occurs at the serine and tyrosine residues of histones, and is involved in phosphorylation-dependent signaling during exercise.

Micro-RNAs are small non-coding RNAs that generally repress the expression of several genes at a post-transcriptional level.
MyomiRs (micro-RNAs arising from skeletal or cardiac muscle) have been identified, including miR-1, miR-133a, miR-133b, miR-206, miR-208b, miR-486, and miR-499.
MyomiRs' functions are to control the biogenesis, regeneration, and maintenance of the skeletal muscle tissue.